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WO2008060609A1 - Formes cristallines d'ibandronate sodique - Google Patents

Formes cristallines d'ibandronate sodique Download PDF

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Publication number
WO2008060609A1
WO2008060609A1 PCT/US2007/024048 US2007024048W WO2008060609A1 WO 2008060609 A1 WO2008060609 A1 WO 2008060609A1 US 2007024048 W US2007024048 W US 2007024048W WO 2008060609 A1 WO2008060609 A1 WO 2008060609A1
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WO
WIPO (PCT)
Prior art keywords
ibandronate sodium
crystalline form
ray powder
powder diffraction
diffraction reflections
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2007/024048
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English (en)
Inventor
Eran Turgeman
Revital Lifshitz-Liron
Claude Singer
Tamás KOLTAI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceutical Industries Ltd
Teva Pharmaceuticals USA Inc
Original Assignee
Teva Pharmaceutical Industries Ltd
Teva Pharmaceuticals USA Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Teva Pharmaceutical Industries Ltd, Teva Pharmaceuticals USA Inc filed Critical Teva Pharmaceutical Industries Ltd
Priority to EP07853128A priority Critical patent/EP1966227A1/fr
Priority to JP2008544678A priority patent/JP2009516004A/ja
Publication of WO2008060609A1 publication Critical patent/WO2008060609A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • the invention encompasses crystalline forms of ibandronate sodium, as well as processes for the preparation thereof.
  • Ibandronate sodium (l-hydroxy-3-(N-methyl-N-pentylamino)propylidene) bisphosphonic acid monosodium salt, is a third-generation nitrogen-containing bisphosphonate characterized by an aliphatic tertiary amine side chain.
  • Ibandronate sodium is typically a white powder.
  • Ibandronate sodium has the empirical formula
  • Ibandronate sodium is currently marketed in the United States by Hoffmann-La Roche under the tradename BONIV A ® in its monohydrate form.
  • BONIV A ® is indicated for the treatment and prevention of osteoporosis in post-menopausal women.
  • BONTV A ® is available as an intravenous injection administered every 2-3 months or as an oral formulation.
  • BONIV A ® is marketed in Europe under the tradename BONDRONAT ® for the treatment of skeletal-related events in patients with breast cancer and bone metastases.
  • BONDRONAT is available in an ampoule with 1 ml concentrate for solution for infusion; 1 ml of solution is reported to contain 1.125 mg of ibandronic monosodium salt monohydrate, corresponding to 1 mg of ibandronic acid.
  • Ibandronate salts such as ibandronate sodium, are generally prepared from ibandronic acid (“IBD-Ac”), which has the following chemical structure:
  • Ibandronic acid U.S. Patent No. 4,927,814 discloses diphosphonic acids, such as ibandronic acid, derivatives thereof, processes for preparing the acids and derivatives, and pharmaceutical compositions containing them.
  • the invention relates to the solid state physical properties of ibandronate sodium. These properties can be influenced by controlling the conditions under which ibandronate sodium is obtained in solid form.
  • Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must necessitate the use of glidants such as colloidal silicon dioxide, talc, starch, or tribasic calcium phosphate.
  • Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid.
  • the rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally administered active ingredient can reach the patient's bloodstream.
  • the rate of dissolution is also a consideration in formulation syrups, elixirs, and other liquid medicaments.
  • the solid state form of a compound can also affect its behavior on compaction and its storage stability.
  • polymorphic form can give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”) and can be used to distinguish some polymorphic forms from others.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • a particular polymorphic form can also give rise to distinct spectroscopic properties that can be detectable by powder x-ray crystallography, solid state 13 C NMR spectroscopy, and infrared spectrometry.
  • a crystalline solid has improved chemical and physical stability over the amorphous form, and forms with low crystallinity. Crystalline forms may also exhibit improved solubility, hygroscopicity, bulk properties, and/or flowability.
  • PCT Publication No. WO 2006/024024 refers to several crystalline forms of ibandronate sodium and processes for their preparation.
  • the invention encompasses a crystalline form of ibandronate sodium denominated Form V.
  • Form V is characterized by x-ray powder diffraction reflections at 5.3, 17.2, 17.8 and 18.4 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline ibandronate sodium Form V may be prepared by a process comprising storing ibandronate sodium Form C at about 20°C to about 3O 0 C for more than about 3 months.
  • the crystalline ibandronate sodium Form V may be prepared by a process comprising storing ibandronate sodium Form H at about 20 0 C to about 30 0 C, for more than about 3 months.
  • the crystalline ibandronate sodium Form V may also be prepared by a process comprising: slurrying ibandronic acid and 1-propanol or 2-propanol; heating; adding and a base selected from the group consisting of: sodium tetraborate and sodium acetate; and cooling to obtain a precipitate.
  • the invention encompasses a crystalline form of ibandronate sodium denominated Form W.
  • Form W is characterized by x-ray powder diffraction reflections at 5.4, 11.4, 16.5 and 17.5 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline ibandronate sodium Form W may be prepared by a process comprising: combining ibandronic acid, water, and a base selected from the group consisting of sodium hydroxide, Na 2 CO 3 , NaHCO 3 , and NaOAc to obtain a solution; and combining the solution with isopropyl alcohol ("IPA") to obtain the crystalline ibandronate sodium Form W.
  • IPA isopropyl alcohol
  • the present invention encompasses a crystalline form of ibandronate sodium denominated Form L.
  • Form L is characterized by x-ray powder diffraction reflections at 5.0, 10.9, 13.8 and 17.7 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline ibandronate sodium Form L is prepared by a process comprising slurrying ibandronate sodium in 2-butanol.
  • the invention encompasses a process for preparing crystalline ibandronate sodium Form G comprising combining ibandronate sodium and a solvent selected from the group consisting of dimethylsulfoxide ("DMSO”) and ethanol to obtain a slurry of the crystalline ibandronate sodium Form G.
  • DMSO dimethylsulfoxide
  • the invention also encompasses a process for preparing crystalline ibandronate sodium Form Q comprising storing crystalline ibandronate sodium Form Q2, Form R, or Form S at a temperature of about 15°C to about 30°C for more than about 3 months.
  • the invention encompasses a process for preparing crystalline ibandronate sodium Form QQ comprising storing crystalline ibandronate sodium crystalline Form F or Form L at about room temperature for more than about 3 months.
  • the invention encompasses a process for preparing crystalline ibandronate sodium Form QQ comprising storing crystalline ibandronate sodium Form Q, Form Q3, Form Q4, Form K, or Form K3 at about room temperature for about one week at about 60-100 % RH.
  • the invention encompasses a process for preparing crystalline ibandronate sodium Form T comprising storing amorphous ibandronate sodium at about room temperature for more than about 3 months.
  • the invention encompasses a process for preparing crystalline ibandronate sodium Form Q4 comprising storing crystalline ibandronate sodium Form Q3 at about room temperature for more than about 3 months.
  • the invention encompasses a process for preparing crystalline ibandronate sodium Form C comprising suspending ibandronic acid Form Sl in n-butanol or 2-butanol; heating the suspension; adding sodium tetraborate decahydrate to the suspension to obtain ibandronate sodium; and cooling the suspension to obtain a precipitate of the crystalline ibandronate sodium Form C.
  • the invention encompasses crystalline ibandronate sodium Forms L, G, V, or W having a maximal particle size of less than about 500 ⁇ m, more preferably less than about 300 ⁇ m, even more preferably less than about 200 ⁇ m, even more preferably less than about 100 ⁇ m, and most preferably less than about 50 ⁇ m.
  • the invention encompasses a pharmaceutical formulation comprising at least one of the above-described crystalline ibandronate sodium Forms V, W, or L and at least one pharmaceutically acceptable excipient.
  • the invention encompasses a process for preparing a pharmaceutical formulation comprising combining at least one of the above-described crystalline ibandronate sodium Forms V, W, or L with at least one pharmaceutically acceptable excipient.
  • the invention encompasses the use of the above-described crystalline ibandronate sodium Forms V, W, or L in the manufacture of a pharmaceutical composition. In another embodiment, the invention encompasses at least one of the above- described crystalline ibandronate sodium Forms V, W, or L for use in treating or preventing skeletal-related events, preferably wherein the skeletal-related event is osteoporosis.
  • Figure 1 illustrates a characteristic x-ray powder diffractogram of crystalline ibandronate sodium Form L.
  • Figure 2 illustrates a characteristic x-ray powder diffractogram of crystalline ibandronate sodium Form G.
  • Figure 3 illustrates a characteristic x-ray powder diffractogram of crystalline ibandronate sodium Form V.
  • Figure 4 illustrates a characteristic x-ray powder diffractogram of crystalline ibandronate sodium Form W.
  • the invention addresses a need in the art by providing additional crystalline forms of ibandronate sodium, as well as processes for their preparation.
  • the invention also provides additional processes for preparing known crystalline forms of ibandronate sodium.
  • room temperature refers to a temperature of about 15 0 C to about 30°C.
  • PCT Publication No. WO 2006/024024 (“WO '024"), hereby incorporated by reference, refers to the following crystalline forms of ibandronate sodium, as well as processes for preparing them: Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, Form K2, Form K3, Form Q, Form Ql , Form Q2, Form Q3, Form Q4, Form Q5, Form Q6, Form QQ, Form R, Form S, Form T.
  • WO '024 reports several characteristic powder x-ray diffraction ("PXRD”) reflections for each crystalline form of ibandronate sodium. These characteristic reflections are summarized in Table 1 below.
  • Forms C, D, E, F, G, H, J, K, K2, K3, Q, Ql, Q2, Q3, Q4, Q5, Q6, QQ, R, S, and T of ibandronate sodium are as defined in WO2006024024, and can be made by the processes disclosed therein.
  • ibandronic acid Forms C, D, E, F, G, H, J, K, K2, K3, Q, Ql, Q2, Q3, Q4, Q5, Q6, QQ, R, S, and T are characterized by the "primary" PXRD peaks as listed in the second column of Table 1 above, and may further be characterized by the "secondary" PXRD peaks listed in the third column of Table 1 above.
  • the invention encompasses additional crystalline forms of ibandronate sodium, denominated Forms V, W, and L.
  • the invention encompasses a crystalline form of ibandronate sodium denominated Form V.
  • Form V is characterized by x-ray powder diffraction reflections at 5.3, 17.2, 17.8 and 18.4 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • Form V can be further characterized by x-ray powder diffraction reflections at 19.6 and 21.2°2 ⁇ ⁇ 0.2 °2 ⁇ .
  • Figure 3 illustrates a representative powder x-ray diffraction diagram for Form V.
  • the crystalline ibandronate sodium Form V may be a solvate of 1-butanol, and may contain about 15 % of 1 -butanol by weight as determined by Thermal Gravimetric Analysis (TGA).
  • the crystalline bandronate sodium Form V may also be a solvate of 1 or 2-propanol and may contain about 16 % of 1 or 2-propanol, respectively, by weight as determined by TGA.
  • the crystalline ibandronate sodium Form V may be a monobutanolate, monopropanolate or monoisopropanolate.
  • the crystalline ibandronate sodium Form V may be prepared by a process comprising storing crystalline ibandronate sodium Form C at about 2O 0 C to about 3O 0 C for more than about 3 months.
  • the temperature is about room temperature.
  • the ibandronate sodium Form C is stored at a relative humidity of about 40% to about 80%, and more preferably about 50% to about 70%.
  • the crystalline ibandronate sodium Form C is stored for about 2 years.
  • the crystalline ibandronate sodium Form V may be prepared by a process comprising storing ibandronate sodium Form H at about 20°C to about 30°C, and preferably at about room temperature, for more than about 3 months.
  • the crystalline ibandronate sodium Form V is stored at a relative humidity of about 40% to about 80%, and preferably about 50% to about 70%.
  • the ibandronate sodium Form H is stored for about 2 years.
  • the crystalline ibandronate sodium Form V may be prepared by a process comprising slurrying ibandronic acid and 1-propanol or 2-propanol; heating the slurry; adding to the slurry a base selected from the group consisting of sodium tetraborate and sodium acetate; and cooling the slurry to obtain a precipitate of the crystalline ibandronate sodium Form V.
  • the slurry Prior to the heating step, the slurry is typically stirred.
  • the slurry is heated to about 75 0 C to about 100°C, and more preferably to about reflux temperature.
  • the slurry is typically stirred while heating.
  • the slurry is stirred while heating for about 1 hour to about 5 hours prior to the cooling step.
  • the slurry is cooled to about 3O 0 C to about 5°C, and more preferably to about room temperature.
  • the slurry is typically stirred while cooling.
  • the slurry is stirred while cooling for about 10 hours to about 20 hours, and more preferably to about 16 hours.
  • the precipitated crystalline ibandronate sodium Form V may be recovered from the slurry by any method known to one of ordinary skill in the art.
  • the crystalline ibandronate sodium Form V is recovered by collecting the precipitate of crystalline ibandronate sodium Form V from the slurry by filtration, washing the precipitate, and drying the precipitate.
  • the precipitate is washed with the same solvent used in the process.
  • the precipitate is dried under vacuum with heating, preferably at a temperature of about 3O 0 C to about 6O 0 C, and more preferably at about 5O 0 C.
  • the drying is done under a pressure of about 20 to about 30 mbar.
  • the precipitate may be dried for about 19 hours to about 25 hours.
  • the invention also encompasses a crystalline form of ibandronate sodium denominated Form W.
  • Form W is characterized by x-ray powder diffraction reflections at 5.4, 11.4, 16.5 and 17.5 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • Form W can be further characterized by x-ray powder diffraction reflections at 19.0 and 20.2 ⁇ 0.2 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • Figure 4 illustrates a representative powder x-ray diffraction diagram for Form W.
  • the crystalline ibandronate sodium Form W may be prepared by a process comprising: combining ibandronic acid, water, and a base selected from the group consisting of sodium hydroxide, Na 2 CO 3 , NaHCO 3 , and NaOAc to obtain a solution; and combining the solution with isopropyl alcohol ("IPA") to obtain the crystalline ibandronate sodium Form W.
  • IPA isopropyl alcohol
  • the combination of the ibandronic acid, water, and base is heated while stirring to obtain the solution.
  • the combination of the ibandronic acid, water, and base is heated at a temperature of about 7O 0 C to about 8O 0 C, and more preferably at a temperature of about 72°C.
  • the solution is combined with the isopropyl alcohol by adding the solution to the isopropyl alcohol.
  • the isopropyl alcohol is cooled prior to combining with the solution.
  • the isopropyl alcohol is cooled to a temperature of about O 0 C to about -1O 0 C, and more preferably to a temperature of about -2 0 C.
  • combining the solution with the isopropyl alcohol produces a mixture containing a precipitate of the crystalline ibandronate sodium Form W.
  • the mixture is stirred while cooling prior to recovering the crystalline ibandronate sodium Form W from the mixture.
  • the mixture is stirred for about 10 hours to about 24 hours, more preferably for about 15 hours to about 24 hours, and most preferably for about 17 hours.
  • the mixture is cooled to a temperature of about -5°C to about 5°C, and more preferably to a temperature of about O 0 C.
  • the crystalline ibandronate sodium Form W may be recovered from the mixture by any method known to one of ordinary skill in the art.
  • the crystalline ibandronate sodium Form W is recovered by collecting the precipitate of crystalline ibandronate sodium Form W from the mixture by filtration, and drying the precipitate.
  • the precipitate is dried in a vacuum oven at a temperature of about 50 0 C to about 80 0 C, and more preferably at a temperature of about 50 0 C, for about 20 hours to about 30 hours, and more preferably for about 24 hours.
  • the drying is done under a pressure of about 10-200 mm Hg.
  • the invention also encompasses a crystalline form of ibandronate sodium denominated Form L.
  • Form L is characterized by x-ray powder diffraction reflections at 5.0, 10.9, 13.8 and 17.7 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • Form L can be further characterized by an x-ray powder diffraction reflection at 27.9 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • Figure 1 illustrates a representative powder x-ray diffraction diagram for Form L.
  • the crystalline ibandronate sodium Form L is prepared by a process comprising slurrying crystalline ibandronate sodium Form QQ in 2-butanol.
  • the slurry of the ibandronate sodium in 2-butanol is maintained, with stirring, for a period of time sufficient to obtain the crystalline ibandronate sodium Form L.
  • the slurry is maintained, with stirring, for about 0 to about 24 hours, and more preferably for about 22 hours, to obtain the crystalline ibandronate sodium Form L.
  • the slurry is maintained at a temperature of about 100 0 C to about 110 0 C, and more preferably at about reflux temperature.
  • the crystalline ibandronate sodium Form L may be recovered from the slurry by any method known to one of ordinary skill in the art.
  • the crystalline ibandronate sodium Form L is recovered by collecting the precipitate from the slurry by filtration, washing the precipitate, and drying the precipitate.
  • the precipitate is washed with 2-butanol.
  • the precipitate is dried in a vacuum oven at a temperature of about 50 0 C to about 80 0 C, and more preferably at a temperature of about 5O 0 C.
  • the drying is done under a pressure of about 10 mmHg to 200mmHg.
  • the drying is performed until a constant weight is obtained. More preferably, the drying is performed for about 10 hours to about 48 hours, and preferably for about 24 hours.
  • the invention also encompasses additional processes for preparing the crystalline ibandronate sodium Forms G, Q, QQ, T, Q4, and C referred to in WO '024.
  • the invention encompasses a process for preparing crystalline ibandronate sodium Form G comprising combining ibandronate sodium and a solvent selected from the group consisting of dimethylsulfoxide ("DMSO”) and ethanol to obtain a slurry of the crystalline ibandronate sodium Form G.
  • DMSO dimethylsulfoxide
  • the slurry is maintained, preferably with stirring, for a period of time sufficient to obtain the crystalline ibandronate sodium Form G.
  • the slurry is maintained with stirring for about 20 hours to about 30 hours, and more preferably for about 24 hours to about 26 hours, to obtain the crystalline ibandronate sodium Form G.
  • the slurry is maintained at about room temperature.
  • the crystalline ibandronate sodium Form G may be recovered by any method known to one of ordinary skill in the art.
  • the crystalline ibandronate sodium Form G is recovered by collecting the precipitate from the slurry by filtration, washing the precipitate, and drying the precipitate.
  • the precipitate is washed with the same solvent used to prepare the slurry.
  • the precipitate is dried under vacuum with heating, preferably at a temperature of about 50 0 C to about 80 0 C, and more preferably at a temperature of about 5O 0 C.
  • the drying is done under a pressure of about 10-200 mm Hg.
  • the invention also encompasses a process for preparing crystalline ibandronate sodium Form Q comprising storing crystalline ibandronate sodium Form Q2, Form R, or Form S at a temperature of about 15°C to about 30°C for more than about 3 months.
  • the ibandronate sodium is stored at about room temperature.
  • the ibandronate sodium is stored for about 2 years.
  • the crystalline ibandronate sodium Form Q2, Form R, or Form S may be prepared by the processes provided in WO '024.
  • the invention also encompasses a process for preparing crystalline ibandronate sodium Form QQ comprising storing crystalline ibandronate sodium crystalline Form F or Form L at about room temperature for more than about 3 months.
  • the ibandronate sodium is stored at about room temperature.
  • the ibandronate sodium is stored for about 2 years.
  • the crystalline ibandronate sodium Form F may be prepared by the process provided in WO '024.
  • the invention also encompasses a process for preparing crystalline ibandronate sodium Form QQ comprising storing crystalline ibandronate sodium Form Q, Form Q3, Form Q4, Form K, or Form K3 at about room temperature for about one week at about 60-100 % relative humidity.
  • the crystalline ibandronate sodium Form Q, Form Q3, Form Q4, Form K, or Form K3 may be prepared by the processes provided in WO '024.
  • the invention also encompasses a process for preparing crystalline ibandronate sodium Form T comprising storing amorphous ibandronate sodium at about room temperature for more than about 3 months.
  • the ibandronate sodium is stored for about 2 years.
  • the amorphous ibandronate sodium may be prepared by the process provided in WO '024.
  • the invention also encompasses a process for preparing crystalline ibandronate sodium Form Q4 comprising storing crystalline ibandronate sodium Form Q3 at about room temperature for more than about 3 months.
  • the ibandronate sodium is stored for about 2 years.
  • the crystalline ibandronate sodium Form Q3 may be prepared by the process provided in WO '024.
  • the invention also encompasses a process for preparing crystalline ibandronate sodium Form C comprising suspending ibandronic acid Form S 1 in n-butanol or 2- butanol; heating the suspension; adding sodium tetraborate decahydrate to the suspension to obtain ibandronate sodium; and cooling the suspension to obtain a precipitate of the crystalline ibandronate sodium Form C.
  • the ibandronic acid Form Sl may be prepared by the process disclosed in PCT Publication No. WO 2006/002348, hereby incorporated by reference.
  • Ibandronic acid Form S 1 is typically characterized by x-ray powder diffraction reflections at 8.2, 11.5, 11.9, 13.9, 18.6 and 22.2 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the suspension Prior to the heating step, the suspension is typically stirred. Preferably, the suspension is heated to a temperature of about 85 0 C to about 115°C, and more preferably to a temperature of about 114°C
  • the suspension is typically stirred while heating. Preferably, the suspension is stirred while heating for about 1 hour to about 5 hours prior to the cooling step.
  • the suspension is cooled to a temperature of about 30 0 C to about 10 0 C, and more preferably to about room temperature.
  • the suspension is typically stirred while cooling.
  • the suspension is stirred while cooling for about 10 hours to about 24 hours, and more preferably for about 16 hours.
  • the precipitated crystalline ibandronate sodium Form C may be recovered from the suspension by any method known to one of ordinary skill in the art.
  • the crystalline ibandronate sodium Form C is recovered by collecting the precipitate of crystalline ibandronate sodium Form C from the suspension by filtration, washing the precipitate, and drying the precipitate.
  • the precipitate is washed with n- butanol.
  • the precipitate is dried under vacuum with heating, preferably at a temperature of about 85°C to about 115°C, and more preferably at a temperature of about 50 0 C.
  • the precipitate may be dried for about 19 hours to about 20 hours.
  • the drying is done under a pressure of about 10-200 mm Hg. Crystalline ibandronate sodium Forms D, J, E, QQ, K3, Q4, G, K and Q6 were found to be stable at a temperature of about 15°C to about 30 0 C for more than about 3 months, as described in Example 7 below.
  • the invention also encompasses crystalline ibandronate sodium Forms L, G, V, or W having a maximal particle size of less than about 500 ⁇ m, more preferably less than about 300 ⁇ m, even more preferably less than about 200 ⁇ m, even more preferably less than about 100 ⁇ m, and most preferably less than about 50 ⁇ m.
  • maximal particle size when used to described a sample of crystalline ibandronate sodium, means that 99% of the particles in the sample have a particle size of less than or equal to the maximal particle size.
  • the particle size of the ibandronate sodium crystalline forms may be measured by methods such as sieves, sedimentation, electrozone sensing (coulter counter), microscopy, and/or Low Angle Laser Light Scattering (LALLS).
  • the invention also encompasses a pharmaceutical formulation comprising at least one of the above-described crystalline ibandronate sodium Forms V, W, or L, and at least one pharmaceutically acceptable excipient.
  • the invention further encompasses a process for preparing a pharmaceutical formulation comprising combining at least one of the above-described crystalline ibandronate sodium Forms V, W, or L with at least one pharmaceutically acceptable excipient.
  • the invention further encompasses the use of the above-described crystalline ibandronate sodium Forms V, W, or L in the manufacture of a pharmaceutical composition.
  • Pharmaceutical formulations of the invention contain crystalline ibandronate sodium, such as one of the above-described forms, and optionally one or more other forms of ibandronate sodium.
  • the pharmaceutical formulations of the invention can contain one or more excipients. Excipients are added to the formulation for a variety of purposes. Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g.
  • AVICEL ® microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. EUDRAGIT ® ), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
  • EUDRAGIT ® polymethacrylates
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. CARBOPOL ® ), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. KLUCEL ® ), hydroxypropyl methyl cellulose (e.g.
  • METHOCEL ® liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. KOLLEDON ® , PLASDONE ® ), pregelatinized starch, sodium alginate, and starch.
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. AC-DI-SOL ® , PRMELLOSE ® ), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g.
  • KOLLIDON ® KOLLIDON ® , POLYPLASDONE ®
  • guar gum magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. EXPLOTAB ® ), and starch.
  • Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
  • Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
  • a dosage form such as a tablet
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
  • Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
  • Solid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • the solid compositions of the invention include powders, granulates, aggregates, and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration.
  • the dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
  • Solid dosage forms include tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as suspensions.
  • the dosage form of the invention can be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
  • the shell can be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • compositions and dosage forms can be formulated into compositions and dosage forms according to methods known in the art.
  • a composition for tableting or capsule filling can be prepared by wet granulation.
  • wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules.
  • the granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size.
  • the granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.
  • a tableting composition can be prepared conventionally by dry blending.
  • the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules.
  • the compacted granules can subsequently be compressed into a tablet.
  • a blended composition can be compressed directly into a compacted dosage form using direct compression techniques.
  • Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
  • a capsule filling of the invention can comprise any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.
  • the invention also encompasses methods of treating or preventing skeletal - related events, such as osteoporosis, comprising administering a pharmaceutical formulation comprising a therapeutically effective amount of at least one of the above- described crystalline forms of ibandronate sodium and at least one pharmaceutically acceptable excipient to a patient in need thereof.
  • Ibandronate sodium may be formulated for administration to a mammal, preferably a human, by injection.
  • the crystalline ibandronate sodium can be formulated, for example, as a suspension for injection.
  • the formulation can contain one or more solvents.
  • a suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity.
  • Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. See, e.g., Ansel, H.C., et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (7th ed. 1999), which is incorporated herein by reference.
  • BONIV A ® and/or BONDRONAT ® can be used as guidance for formulation.
  • BONIVA ® is available as an intravenous injection administered every 2-3 months and as an oral formulation.
  • BONDRONAT ® is available in ampoule with 1 ml concentrate for solution for infusion. 1 ml of the solution contains 1.125 mg of ibandronic monosodium salt monohydrate, corresponding to 1 mg of ibandronic acid.
  • the x-ray powder diffraction was performed on Scintag X-ray powder diffractometer model X' TRA with a solid state detector at room temperature. Copper radiation of 1.5418 A was used.
  • the sample holder was a round standard aluminum sample holder with rough zero background.
  • the scanning parameters were range: 2-40 degrees two-theta; scan mode: continuous scan; step size: 0.05 degrees; and at a rate of 5 degrees/minute.
  • LOD Loss on Drying
  • TGA Thermal Gravimetric Analysis
  • Example 1 Process for preparing crystalline ibandronate sodium Form L
  • Ibandronate Sodium (3.0 g) was stirred in 2-Butanol (32 ml) at reflux temperature for 22 hours. The slurry was cooled to room temperature. The white solid was isolated by vacuum filtration, washed with 2-Butanol (2x25 ml) and dried in a vacuum oven at 5O 0 C for 20 hours to obtain 3.0 g of crystalline ibandronate sodium form L.
  • Example 2 Process for preparing crystalline ibandronate sodium Form G
  • Ibandronate Sodium (3.0 g) was stirred in DMSO (20 ml) at room temperature for 26 hours. The gelatinous product was then isolated by vacuum filtration, washed with DMSO (2 ml) and dried in a vacuum oven at 5O 0 C for 24 hours to obtain 3.3 g of crystalline ibandronate sodium Form G.
  • Example 3 Process for preparing crystalline ibandronate sodium Form G
  • Ibandronate Sodium (3.0 g) was stirred in Ethanol (20 ml) at room temperature for 25 hours. The white solid was then isolated by vacuum filtration, washed with Ethanol (2x5 ml) and dried in a vacuum oven at 5O 0 C for 24 hours to obtain 3.4 g of crystalline ibandronate sodium Form G.
  • Example 4 Process for preparing crystalline ibandronate sodium Form G
  • Ibandronate Sodium (3.0 g) was stirred in DMSO (5 ml) at room temperature for 25 hours. The gelatinous product was then isolated by vacuum filtration, washed with DMSO (6 ml) and dried in a vacuum oven at 50°C for 24 hours to obtain 3.2 g of crystalline ibandronate sodium Form G.
  • Example 5 Process for preparing crystalline ibandronate sodium Form V
  • Crystalline ibandronate sodium Form C was stored at room temperature for 2 years. The sample was retested after the storage time and found to be crystalline ibandronate sodium Form V by XRD.
  • Example 6 Process for preparing Ibandronate sodium Form V
  • Crystalline ibandronate Sodium Form H was stored at room temperature for 2 years. The sample was retested after the storage time and found to be a mixture of crystalline ibandronate sodium Forms H and V by XRD.
  • Example 7 Stability of crystalline forms of ibandronate sodium when stored for 2 years at room temperature
  • Table 2 summarizes the results before and after the storage.
  • Forms D, J, E, QQ, K3, Q4, G, K, and Q6 maintained their crystalline form after storage at room temperature for two years.
  • Example 8 Stability of crystalline forms of ibandronate sodium when stored at 0-100 % relative humidity
  • Table 3 summarizes the results before and after the storage.
  • Example 9 Process for preparing crystalline ibandronate sodium Form W
  • Example 10 Process for preparing crystalline ibandronate sodium Form C Ibandronic Acid Form Sl (5.0g) was stirred in n-butanol (100ml) at 114 0 C. To the obtained partial solution, sodium tetraborate decahydrate (3g, leq) was added. The obtained slurry was stirred at 114 0 C for 3 hours and then it was cooled to room temperature. The slurry was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with n-butanol (2x5ml) and dried in a vacuum oven at 5O 0 C for 19.5 hours to obtain 6.2g of crystalline ibandronate sodium Form C.
  • Example 11 Process for preparing crystalline Ibandronate sodium Form V
  • Ibandronic Acid 5.0g was stirred in 1-Propanol (100ml) at reflux temperature.
  • Sodium tetraborate (1.6g, l/2eq) (prepared according to examples 11 (a) and l l(b)) was added.
  • the slurry was stirred for 4 hours at reflux temperature. Then the slurry was cooled to room temperature. The slurry was stirred at room temperature for 16 hours.
  • the precipitate was isolated by vacuum filtration, washed with 1-Propanol (2x5ml) and dried in a vacuum oven at 5O 0 C for 24 hours to obtain 6g of crystalline Ibandronate Sodium Form V.
  • Example l l(a) Process for preparing sodium tetraborate anhydrous
  • Example 1 Kb Process for preparing sodium tetraborate anhydrous Sodium tetraborate decahydrate (Aldrich) (5g) and Toluene (Tech) (50ml) were stirred with a mechanical stirrer and heated to reflux for azeotropic distillation with a dean stark apparatus for 4 hours. The slurry was cooled to room temperature and stirred at room temperature over the weekend. The slurry was then evaporated until dryness to give 3g sodium tetraborate anhydrous.
  • Example 12 Process for preparing crystalline Ibandronate sodium Form V
  • Ibandronic Acid 5.0g was stirred in 2-Propanol (100ml) at reflux temperature.
  • Sodium tetraborate (1.6g, l/2eq) (prepared according to example 12(a)) was added.
  • the slurry was stirred for 4 hours at reflux temperature. Then the slurry was cooled to room temperature. The slurry was stirred at room temperature for 16 hours.
  • the precipitate was isolated by vacuum filtration, washed with 2-Propanol (2x1 OmI) and dried in a vacuum oven at 5O 0 C for 24 hours to obtain 2.15g of crystalline Ibandronate Sodium form V.
  • Example 12(a) Process for preparing sodium tetraborate anhydrous Sodium tetraborate decahydrate (Aldrich) (2Og) and Toluene (Tech) (100ml) were stirred with mechanical stirrer and heated to reflux for azeotropic distillation with a dean stark apparatus for 3 hours. The slurry was cooled to room temperature and evaporated until dryness to give 13.45g sodium tetraborate anhydrous.
  • Example 13 Process for preparing Ibandronate sodium Form V
  • Ibandronic Acid 5.0g was stirred in 2-Propanol (100ml) at reflux temperature.
  • Sodium acetate (1.3g, leq) (prepared according to example 13(a)) was added.
  • the slurry was stirred for 4 hours at reflux temperature. Then the slurry was cooled to room temperature. The slurry was stirred at room temperature for 16 hours.
  • the precipitate was isolated by vacuum filtration, washed with 2-Propanol (2x5ml) and dried in a vacuum oven at 5O 0 C for 24 hours to obtain 6g of crystalline Ibandronate Sodium Form V.

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Abstract

L'invention concerne des formes cristallines d'ibandronate sodique ainsi que leurs procédés de préparation.
PCT/US2007/024048 2006-11-16 2007-11-16 Formes cristallines d'ibandronate sodique Ceased WO2008060609A1 (fr)

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EP07853128A EP1966227A1 (fr) 2006-11-16 2007-11-16 Formes cristallines d'ibandronate sodique
JP2008544678A JP2009516004A (ja) 2006-11-16 2007-11-16 イバンドロン酸ナトリウムの結晶形態

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WO2008131160A1 (fr) * 2007-04-19 2008-10-30 Dr. Reddy's Laboratories Ltd. Polymorphes de l'ibandronate sodique
WO2009053445A3 (fr) * 2007-10-26 2009-10-15 Chemo Ibérica, S.A. Formes polymorphes d'ibandronate sodium et leurs procédés de préparation

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US20060172976A1 (en) * 2005-02-01 2006-08-03 Uwe Eiermann Ibandronate polymorph
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WO2006024024A2 (fr) * 2004-08-23 2006-03-02 Teva Pharmaceutical Industries Ltd. Sodium d'ibandronate solide cristallin et ses procedes de preparation
WO2006045578A2 (fr) * 2004-10-29 2006-05-04 F. Hoffmann-La Roche Ag Procede servant a preparer des bisphosphonates
US20060172976A1 (en) * 2005-02-01 2006-08-03 Uwe Eiermann Ibandronate polymorph
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CHIKHALE E: "BONIVA (ibandronate sodium) Tablets 2.5 mg", INTERNET CITATION, 2 July 2003 (2003-07-02), XP002427781, Retrieved from the Internet <URL:http://www.fda.gov/cder/foi/nda/2003/21-455_Boniva_chemr.pdf> [retrieved on 20070403] *
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008131160A1 (fr) * 2007-04-19 2008-10-30 Dr. Reddy's Laboratories Ltd. Polymorphes de l'ibandronate sodique
WO2009053445A3 (fr) * 2007-10-26 2009-10-15 Chemo Ibérica, S.A. Formes polymorphes d'ibandronate sodium et leurs procédés de préparation

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EP1966227A1 (fr) 2008-09-10

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